Schizophrenia (SCZ) is a common, lifelong, disabling disorder with unsatisfactory treatment, motivating research into its causation and pathogenesis. The heritability of SCZ is estimated at over 70%, yet recent GWAS mega analyses have explained a relatively small fraction of the heritability. Another portion of the heritability is lkely due to rare loci. Although by definition the rare loci may affect risk in only a small number of individuals, investigations of diseases such as familial hypercholesterolemia show that the rare loci can potentially teach us much about the etiology of disease and even indicate new avenues of treatment. Recent publications support this contention. We propose to identify rare SCZ loci with large effects through highly selected extended pedigrees. We will leverage resources from an ongoing NIH funded Multiplex- Multigenerational Genetic Investigation (MGI). Over the past ten years, through a three- site collaboration, we have identified, intensively characterized and investigated over 43 multiplex, multigenerational SCZ pedigrees and community controls. MGI has a wealth of phenotypic data, including gene expression, structural and functional brain imaging, and neurocognitive performance measures, as well as standard clinical symptom, diagnostic and functional information on participants. From this sample, we have identified four extended families, each with three or more individuals with SCZ and an unusually high number of additional family members with non-SCZ Axis I diagnoses. We aim to identify rare SCZ risk variants in these families using an efficient and cost effective strategy that combines novel founder-specific linkage analyses, whole genome sequencing of selected individuals and panels of selected SNPs. Using the available extensive quantitative data, we will investigate the expression of the risk loci beyond affection status and take a dimensional approach to vulnerability and severity. We will also investigate the expression of the rare variants in neurons differentiated from induced pluripotent stem cells. By investigating a range of highly relevant phenotypes, our proposal aims to go beyond disease gene mapping to initiate an understanding of SCZ pathogenesis. Our consortium brings expertise in SCZ, neurobiology, neurocognition, neuroimaging, and genetics to this effort. We have made all existing tissue samples and data available to the scientific community and will continue to do so.